Original ArticlesInterpretation of Immunohistochemistry for Mismatch Repair Proteins is Only Reliable in a Specialized SettingOverbeek, Lucia I. H. MSc* †; Ligtenberg, Marjolijn J. L. PhD* ‡; Willems, Riki W. BSc‡; Hermens, Rosella P. M. G. PhD†; Blokx, Willeke A. M. MD, PhD‡; Dubois, Stefan V. MD, MSc§; van der Linden, Hans MD, PhD∥; Meijer, Jos W. R. MD, PhD¶; Mlynek-Kersjes, Maria L. MD♯; Hoogerbrugge, Nicoline MD, PhD*; Hebeda, Konnie M. MD, PhD‡; van Krieken, Joannes H. J. M. MD, PhD‡ Author Information Departments of *Human Genetics ‡Pathology †Center for Quality of Care Research, Radboud University Nijmegen Medical Center, Nijmegen §Department of Pathology, Meander Medical Center, Amersfoort ∥Department of Pathology, Jeroen Bosch Hospital, ‘s-Hertogenbosch ¶Department of Pathology, Rijnstate Hospital, Arnhem, Netherlands ♯Department of Pathology, Moers, Germany Correspondence: Joannes H. J. M. van Krieken, MD, PhD, 824 Pathology, Radboud University Nijmegen Medical Center, PO box 9101, 6500 HB Nijmegen, Netherlands (e-mail: [email protected]). The American Journal of Surgical Pathology: August 2008 - Volume 32 - Issue 8 - p 1246-1251 doi: 10.1097/PAS.0b013e31816401bb Buy Metrics Abstract We examined the validity of immunohistochemistry for mismatch repair (MMR) proteins in colorectal cancer specimens to identify patients at risk for Lynch syndrome (hereditary nonpolyposis colorectal cancer) and patients with sporadic microsatellite instable colorectal cancer. This was assessed by observer agreement for and accuracy of interpretation of immunohistochemistry. Seven pathologists from 5 different pathology laboratories evaluated 100 molecularly defined colorectal cancers stained for MLH1, PMS2, MSH2, and MSH6. Two of the pathologists were experienced in interpretation of immunohistochemistry for MMR proteins. After evaluation of a subset of 20 cases, a discussion meeting was organized, after which pathologists evaluated all 100 cases. Staining patterns were interpreted as aberrant, normal, or indefinite. In 82% of tumors, 5 or more pathologists reached the same interpretation, which was considered the consensus diagnosis. Consensus was reached slightly less frequently in microsatellite instable than in stable tumors, and interobserver variation was moderate to substantial (κ: 0.49-0.79). More microsatellite instable tumors showed an indefinite staining pattern compared with microsatellite stable tumors. Three out of 7 pathologists, including the 2 experienced pathologists, did not miss a microsatellite instable tumor. Each pathologist found at least 1 tumor with an aberrant staining pattern, whereas consensus was a normal staining pattern and the tumor was microsatellite stable. We conclude that, if restricted to experienced pathologists, immunohistochemistry is a valid tool to identify patients at risk for Lynch syndrome and patients with sporadic microsatellite instable colorectal cancer. An indefinite or aberrant staining result has to be followed by molecular microsatellite instability analysis to confirm the presence of a defective DNA MMR system. © 2008 Lippincott Williams & Wilkins, Inc.